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Synthesis and Bioassay of Antagonists of the Luteinizing Hormone Releasing Hormone Having the Azagly10 Moiety

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Synthesis and Bioassay of Antagonists of the Luteinizing Hormone Releasing Hormone Having the Azagly10 Moiety Synthesis and Bioassay of Antagonists of the Luteinizing Hormone Releasing Hormone Having the Azagly10 Moiety Karl Folkers*' + , Cyril Y. Bowers+, Wilson B. Lutz*. Klaus Friebel*, Teresa Kubiak*, Bernhard Schircks*. and Georg Rampold* * Institute for Biomedical Research, The University of Texas at Austin, Austin, Texas 78712, + Tulane University School of Medicine, New Orleans, Louisiana 70112 Z. Naturforsch. 37b, 1075-1081 (1982); received March 23, 1982 Antagonist, Luteinizing Hormone Releasing Hormone, Ovulation, Peptides, Azaglycine Seven new analogs of the luteinizing hormone releasing hormone (LHRH), having an Azagly10 moiety, and three corresponding Gly10-analogs were synthesized for bioassay and comparison of inhibitory potencies. This study was toward a possible advantage of the Azagly10 moiety to minimize C-terminal degradation, in vivo. Of the three procedures which were studied to achieve Azagly10-peptides, the reaction of cyanate ion with hydrazides was the most favorable. Variations of substitution in position 1 were also studied. The data from the antiovulatory assay showed that an Azagly10 moiety may not depress activity, and may allow equal or even higher activity than the Glv10 moiety, depending on the analog. [N-Ac-D-Thr1, D-p-Cl-Phe2, D-Trp3-6, Azagly10] LHRH was more inhibitory than the corresponding Gly10-analog. Based on pairs of analogs, the following relationships appeared: (1) N-Ac-D-Thr1 was more effective than N-Ac-jo-Cl-Phe1; (2) The L-configuration of Ala as N-Ac-Ala1- was more effective than the D—; (3) N-Ac-Ala1 appeared more effective than the N-Ac-D-Thr1; (4) D-Trp6 appeared more effective than D-Phe6. In an ultimate clinical use of an antagonist of LHRH to block ovulation, the Azagly10 moiety may be advantageous for limitation of enzymatic degradation. Introduction important for subsequent studies toward the ulti- The luteinizing hormone releasing hormone mate clinical use of an antagonist of LHRH to (LHRH) functions in the mechanisms of evolution prevent ovulation. and conception. Over a thousand analogs of LHRH have apparently been synthesized, some of which Tab. I. Analogs of LHRH. were significant agonists, super-agonists or antag- onists. 1. [N-Ac-D-^-Cl-Phe1'2,D-Trp3'6,Azagly10]-LHRH We have synthesized and bioassayed a series of 2. [(N-Ac-Pro-Pro)1,D-jo-Cl-Pho2,D-Trp3-6, Azagly10]-LHRH analogs (Table I), most of which have the azaglycine- 3. [(N-Ac-Pro-Pro)1,D-jo-Cl-Phe2,D-Trp3'6]-LHRH amide (Azagly) moiety, I, in position 10. For three 4. [N-Ac-D-Ala1,D-^-Cl-Phe2,D-Trp3-6,Azagly10]- of these analogs, the corresponding peptides having LHRH the glycinamide (Gly) moiety, II, in position 10 5. [N-Ac-Ala1,D-^-Cl-Phe2,D-Trp3'6,Azagly10]- were synthesized for comparison of inhibitory activ- LHRH 6. [N-Ac-D-Thr1,D-p-Cl-Plie2,D-Trp3-6,Azagly10]- ities. LHRH 7. [N-Ac-D-Thr1 ,D-p-Cl-Phe2,D-Trp3.6]-LHRH I, -NH-NH-CO-NHo II, -NH-CH2-CO-NH2 8. [N-Ac-Thr1,D-Phe2,D-Trp3-6,Azagly10]-LHRH The rationale for synthesizing and bioassaying 9. [N-Ac-Thr1,D-Phe2,D-Trp3-6]-LHRH these analogs with Azagly was that the C-terminal 10. [N-Ac-Thr1,D-Phe2-6,D-Trp3,Azagly10]-LHRH might be protected, in vivo, against enzymic degra- dation in contrast to the corresponding Gly10 analogs. Such protection might not be observed by In all of the analogs, the amino acid residues in routine in vivo assays for activity, but might be positions 4, 5, 7, 8, and 9 were identical to those in the same positions of LHRH, i.e., Ser, Tyr, Leu, Arg and Pro. Variations were introduced at posi- * Reprint requests should be sent to Dr. Karl Folkers, tions 1, 2, 3, 6, and 10. N-terminal residues (D-Ala, Institute for Biochemical Research, The University of Texas at Austin, Austin, Texas 78712. L-Ala, D-Thr, D-p-Cl-Phe, L-Thr and the di- 0340-5087/82/0800-1075/$ 01.00/0 peptide L-Pro-L-Pro) were N-acetylated. Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschung This work has been digitalized and published in 2013 by Verlag Zeitschrift in Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung der für Naturforschung in cooperation with the Max Planck Society for the Wissenschaften e.V. digitalisiert und unter folgender Lizenz veröffentlicht: Advancement of Science under a Creative Commons Attribution Creative Commons Namensnennung 4.0 Lizenz. 4.0 International License. 1076 K. Folkers et al. • Luteinizing Hormone Releasing Hormone Variations of the solid phase method of Merrifield method appears to offer advantages for continuation were used to synthesize the peptides. The glycin- of the synthesis of new types of Azagly10-analogs of amide analogs (compounds 3,7, and 9) were prepared LHRH" from benzhydrylamine resins. The azaglvcinamide analogs (compounds 1, 2, 4, 5, 6, 8 and 10) were j I 1-HBT HOAc A N"~CO-NHNH H O ClN-^CO-NHNH-CO-NH. , prepared from chloromethyl Merrifield resins by N C02H CHjCN 2 2 z attaching the penultimate amino acid (Pro) to the 13 resin and completing of the synthesis to the N- terminus. The C-terminal Azagly moiety was then All of the peptides Avere purified by combinations introduced after the peptide was cleaved from the of gel-filtration counter-current distribution (CCD) resin. partition chromatography, and high-performance Two methods for introducing the Azagly residue liquid chromatography (HPLC). were studied. Analogs 4. 6, 8, and 10 were synthe- sized by cleaving the peptide-Merrifield resin with Experimental hydrogen fluoride to give the unprotected N- Amino acid derivatives Avere purchased from acetylated peptide carboxylic acids. Condensation Peninsula Laboratories, San Carlos, California except of the latter with semicarbazide (azaglvcinamide) for D-j9-chlorophenylalanine which Avas proA'ided by by means of N-N'-dicyclohexylcarbodiimide (DCC) the SoutliAvest Foundation for Research and Educa- afforded the peptides for purification. tion. San Antonio, Texas. Alpha amino functions Avere protected by the Boc group except that the Analogs 1,2, and 5 were synthesized by a variation Aoc group AA'as used for arginine. Side chain func- of the azide procedure of Dutta et al. [1] which gave tions Avere protected by Z(Ser,Thr). Tos(Arg) and better yields and fewer difficulties with purification o-Br-Z(Tyr). Benzhydrylamine (BHA) resin AA'as than the method which coupled semicarbazide by purchased from Beckman Bioproducts, Palo Alto. California. DCC, Et3N. CH2C12, and DMF Avere DCC. In this azide procedure, the peptide-Merrifield distilled prior to use. All other chemicals Avere resins were subjected to hydrazinolysis to afford reagent grade. protected peptides as hydrazides. Treatment of these hydrazides with butyl nitrite in acidic dioxan General method of synthesis gave azides which were then allowed to react with The peptides Avere synthesized by the solid phase semicarbazide. The protecting groups were then method using a Beckman Model 990 peptide syn- removed with liquid HF. The conditions of hy- thesizer. Attachment of the first amino acid to a drazinolysis may have possibly resulted in minor loss BHA resin Avas by double DCC-mediated coupling. Attachment of the first amino acid to a chloro- of the N-terminal acetyl group. Phillips [2], and methyl resin AA'as by single coupling of the Boc Schmer and Kreil [3]. have shown that complete amino acid cesium salt. TAVO coupling programs removal of N-acetyl groups by hydrazinolysis is Avere employed for peptide chain elongation. Pro- possible at 100 °C for about 17 h. Ail of the Azagly - gram B Avas identical to Program A except that step 14 was replaced by tAA7o steps, 14 and 15; step 14: containing peptides gave strong positive tests [4] for DMF (3x2 min) and step 15: CH2C12 (3x2 min). hydrazine following complete acid hydrolysis. If a ninhvdrin test [7] indicated an incomplete A new method of introducing the azaglycine acylation of amino groups, a second coupling was performed by a repetition of steps 6 through 14. moiety was extended. Dutta and Morlev [5] reported Sequences resulting from incomplete coupling, even the use of cyanate ion to convert hydrazides to aza- after double coupling Avere terminated by acetyla- amino acid derivatives. In this method, a peptide tion. Acetylation of the N-terminal amino acid hydrazide Avas treated Avith cyanate ion in acidic moiety Avas accomplished by adding 25% acetic solution. We used X-Z-L-proline (11) as a model. anhydride in CHoCL-pyridine in place of steps 10 and 11 of the coupling program. Peptides Avere Condensation of 11 Avith hydrazine by means of removed from BHA resins by treatment with an- DCC in the presence of 1-hydroxybenzotriazole hydrous liquid HF containing ca. 20% anisole for (1-HBT) afforded the N-Z-L-prolvlhydrazide (12), l'h at 0 °C. as described [8], Avhich Avas isolated as the £>-toluene sulfonate salt. TLC was performed on E. Merck silica gel G plates When 12 Avas alloAved to react Avith sodium cyanate Avith detection by fluorescence, chlorine-tolidine spray, and ferric ferricyanide. Values for Rf1, Rf2, in dilute aqueous acetic acid. N-Z-L-prolylaza- Rf3 and A'/4 refer to the systems: 1-butanol-acetic glveinamide (13) Avas formed in high yield. This acid-ethyl acetate-Avater (1:1:3:1), ethanol-Avater 1077 K. Folkers et al. • Luteinizing Hormone Releasing Hormone (7:3); 2-propanol-lM acetic acid (2:1); and 1- Azide couplings butanol-pyridine-acetic acid-water (50:33:1:40). respectively. Optical rotations were measured on a Synthesis of N-Ac-D-p-Cl-Phe-D-p-Cl-Phe-D- Perkin-Elmer Model 141 digital readout Polarimeter.
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